Phenylalanine hydroxylase can be activated not only by its substrate, phenylalanine, but also by other large neutral amino acids. The enzyme can also be activated in vivo by glucagon and the activation is expressed in vivo. Phenylalanine hydroxylase is activated in regenerating liver by a process that probably also involves glucagon. The D-isomer of tetrahydrobiopterin inactivates pure phenylalanine hydroxylase.